Field of Invention
The present invention relates to androstane and pregnane steroid compounds and their use as allosteric modulators of the GABA receptor chloride ionophore complex and their use to alleviate stress, anxiety, mood disorders, seizures, depression, treatment of drug and alcohol abuse, memory, premenstrual disorders, and neural system damage.
Discussion of the Background
The present invention encompasses methods and compounds related to endogenous metabolites of androstane and pregnane steroids. Certain endogenous steroids including allopregnanolone (3α-hydroxy-5α-pregnane-20-one) and the A-ring reduced metabolite of progesterone are potent stereoselective positive allosteric modulators of GABA receptors (Belelli and Lambert, 2005). These neurosteroids, like other agents that potentiate the activity of GABA receptors, exhibit anxiolytic, sedative-hypnotic, anticonvulsant, and general anesthetic actions. Allopregnanolone and A-ring reduced neurosteroids generally lack classical hormonal activity mediated by nuclear hormone receptors. Given their GABA receptor modulating activity, natural neurosteroids could potentially be used therapeutically (Gasior et al., 1999). However, they do not have ideal properties as drug substances. Natural neurosteroids can be metabolically converted to hormonally active substances (Rupprecht, 2003) and have poor bioavailability. Consequently, there is an unmet need for synthetic analogs with improved pharmacokinetic and pharmacodynamic properties. Structural modifications at the 3-position inhibit metabolism of the secondary 3-hydroxyl substituent, but permit GABA receptor modulating activity to be retained (Hogenkamp et al., 1997). One such analog, ganaxalone, the 3β-methyl derivative of allopregnanolone, is currently in clinical development for epilepsy (Monaghan et al., 1999; Rogawski, 2006).
Substitution of the allopregnanolone 17-position with a variety of functional groups allows GABA receptor modulating activity to be retained. For example, the naturally occurring neurosteroids, allotetrahydrodeoxycorticosterone (5α,3α-THDOC), androstenediol, and androsterone, which have O═CCH2OH, alcohol, and keto substituents at the 17-position have GABA receptor modulating activity as does the prototype allopregnanolone, which has an acetyl substituent at the 17-position. In addition, the synthetic 17β-carbonitrile analog exhibits GABA receptor modulatory potency and efficacy similar to allopregnanolone (Wittmer et al., 1996).
Interestingly, the natural (16-17 unsaturated) pheromone, 3α-androstenol, lacks a 17-position substitutent yet retains GABA receptor modulating activity, albeit of reduced potency (Kaminski et al., 2006). Taken collectively, these data indicate a critical role for GABA modulators based on the neuroactive steroid scaffold for treatment of a variety of disease states.